2024 Theses Doctoral
Mechanisms of Transformation in T-Cell Lymphomas: Identification of Therapeutic Targets
T-cell lymphomas (TCLs) are a highly aggressive and heterogeneous group of non-Hodgkin lymphomas derived from post-thymic mature T- and NK-cells broadly classified peripheral (PTCL) or cutaneous (CTCL), indicating either a nodal or skin-homing disease, respectively. One of the main clinical challenges contributing to dismal outcomes for TCL patients is both the lack of curative treatment strategies and the high rate of relapse for currently approved therapies, underscoring the need for identification of novel targeted therapies for the treatment of TCL.
While combination therapeutic strategies have been proposed and show great promise in pre-clinical and clinical trials for PTCL and CTCL, none are yet approved. Additional contributing factors toward the difficulty in studying TCL and the high rate of therapeutic failure is the highly heterogeneous genetic and molecular mechanisms driving TCL as well as the poorly understood role of non-tumor microenvironment cells in the pathogenesis of TCL.
Indeed, while several studies have suggested that tumor associated macrophages play both a significant functional role in supporting tumor maintenance and are therapeutically targetable, less is known about potential tumor supporting roles of other cell microenvironment populations. Here, I used an unbiased and high-throughput approach to discover novel drug combinations in CTCL and to characterize at the single-cell level relevant molecular mechanisms driving T-cell lymphomagenesis.
First, I demonstrate that the combination of romidepsin, a selective class I HDAC inhibitor, with afatinib, an inhibitor of the epidermal growth factor receptor (EGFR) family, produces strongly synergistic antitumor effects in CTCL models, both in vitro and in vivo, using mechanisms of action that involve down-regulation of the JAK-STAT signaling pathway. This result suggests a potential therapeutic role for the combination of HDAC inhibitors with afatinib in the treatment of CTCL that had not been previously recognized.
Second, we developed single-nuclei analysis on a cohort of 30 TCL (PTCL-NOS, AITL, epstein barr virus positive PTCL) and 6 normal patient samples to identify and deconvolute genomic and functional mechanisms contributing to T-cell lymphomagenesis. Here, I implemented a comprehensive bioinformatics pipeline for the analysis of sparse single-nuclei transcriptomic data and characterized heterogeneous molecular mechanisms driving T-cell lymphomagenesis, such as the upregulation of the PI3K-AKT-mTOR and WNT signaling pathways in a subset of 5/9 PTCL-NOS and 7/19 AITL samples, respectively.
Additionally, I identified the enrichment of both the macrophage compartment in PTCL-NOS and AITL, and the specific enrichment of CD8+ T cells in AITL. These results suggest a correlation between patient-specific characteristics, such as mutational status, and possibly therapeutically targetable molecular mechanisms driving neoplastic cell growth that warrants further investigation.
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More About This Work
- Academic Units
- Cellular, Molecular and Biomedical Studies
- Thesis Advisors
- Palomero, Teresa
- Degree
- Ph.D., Columbia University
- Published Here
- February 21, 2024